JPH11104235A - Polysulfone hollow fiber type artificial kidney and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polysulfone type hollow fiber type artificial kidney which has high water permeability, is high in performance to remove uremic substances and is excellent in terms of safety without the admission of permeation of endotoxin even if this artificial kidney has moderate albumin permeability. SOLUTION: This process for production consists in confining the solvent remaining in the hollow fibers of the artificial kidney comprising the hollow fiber membranes consisting of a polysulfone resin contg. a hydrophilic high- molecular material to a specific value or below by washing, then executing a sterilization treatment by using gamma rays and electron beams and insolubilizing the hydrophilic high-molecular material by crosslinking. As a result, the permeability of the albumin is specified to >=0.2 to <=3.0% and the permeability of the endotoxin is suppressed to <=0.02%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a polysulfone hollow fiber artificial kidney used for hemodialysis, hemofiltration or hemofiltration dialysis for prolonging the life of a patient having renal failure or the like, and a method for producing the same. .

[0002]

2. Description of the Related Art Separation membranes made of polysulfone resins have been widely used in various fields because of their good mechanical properties and heat resistance.

[0003] In the field of artificial kidneys as well, separation membranes made of this polysulfone-based resin have excellent ability to remove uremic substances.
-238139 and JP-A-9-70431.

[0004] However, with the increase in long-term dialysis patients, dialysis techniques have been diversified, and higher performance has also been required for artificial kidneys. In other words, very high water permeability is required in online filtration dialysis and push-pull filtration dialysis, and also in ordinary hemodialysis, a high molecular weight of β ₂ -microglobulin and the like can be obtained together with a high ability to remove low molecular substances. There is a demand for a high ability to remove 2,000 or more substances.

[0005] Further, in the past, the permeation of albumin, which is a useful protein in blood, was intended to be suppressed as much as possible. However, it has been found that harmful substances accumulated in dialysis patients are strongly bound to albumin. Therefore, a membrane through which an appropriate amount of albumin can be transmitted is required, and many reports have been made on improvement of symptoms by an artificial kidney using such a membrane. For this reason, the pore size of the separation membrane tends to increase in recent products. With this, back filtration from the dialysate and penetration of endotoxin into the blood side by back diffusion have become a serious problem.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide an artificial kidney having a high water permeability and a high ability to remove uremic substances and an appropriate level of albumin permeability while maintaining the good characteristics of a reverse filtration or reverse filtration. An object of the present invention is to provide a polysulfone-based hollow fiber artificial kidney excellent in safety in which permeation of endotoxin due to diffusion is suppressed and a method for producing the same.

[0007]

The present invention solves the above-mentioned problems. The polysulfone hollow fiber artificial kidney of the present invention has an albumin transmittance of 0.2% or more and 3.0% or more.
Or less and the endotoxin permeability is 0.02%
In the present invention, the albumin transmittance is 0.6% or more.
0% or less, and the endotoxin permeability is preferably 0.01% or less.

[0008] The method for producing a polysulfone hollow fiber artificial kidney of the present invention comprises the steps of: spinning a hollow fiber obtained by spinning a spinning stock solution comprising a polysulfone resin, a water-soluble hydrophilic polymer compound and a solvent. By washing the outer surface of the hollow fiber to remove the hydrophilic polymer compound and the solvent, the hydrophilic polymer compound is localized on the inner surface of the hollow fiber membrane and in the vicinity thereof, and further into a module containing the hollow fiber. The method is characterized by irradiating gamma rays or electron beams in a state filled with water to crosslink and insolubilize the remaining hydrophilic polymer compound at the same time as sterilization.

In the present invention, the ratio of the hydrophilic high molecular compound to the total of the polysulfone resin and the hydrophilic high molecular compound in the spinning dope in the washing of the hollow fiber from the outer surface is C ₁ (% by weight). When the ratio of the hydrophilic polymer compound to the total of the polysulfone-based resin and the hydrophilic polymer compound in the hollow fiber in the module containing the hollow fiber is C ₂ (% by weight), C ₂ / C ₁ Washing until the value becomes 0.1 to 0.5, and in the washing from the outer surface of the hollow fiber, until the solvent component in the filling water in the module storing the hollow fiber becomes 0.5 ppm or less. Washing is preferred.

[0010]

DETAILED DESCRIPTION OF THE INVENTION The polysulfone-based hollow fiber constituting the hollow fiber separation membrane used in the hollow-fiber artificial kidney of the present invention is usually prepared by spinning a spinning stock solution containing a polysulfone-based resin and a hydrophilic polymer compound. Manufactured by In the present invention, finally, the hydrophilic polymer compound is distributed more on the inner surface of the hollow fiber and its vicinity and on the outer surface, and less on the other surface portion and the intermediate layer portion of the hollow fiber, Further, the hydrophilic polymer compound is cross-linked and insolubilized by irradiating gamma rays (γ rays) or electron beams.

In the present invention, it is important to localize the distribution of the hydrophilic polymer compound and sufficiently insolubilize it. As a premise, it is necessary to wash and remove the solvent and the wet holding material used for adjusting the spinning solution remaining inside the hollow fiber membrane before irradiation with gamma rays (γ rays) or electron beams. If the residual amount of the solvent or the moisturizing agent is large, the crosslinking reaction is suppressed. Therefore, as a guide for washing, the sterilized product is left at 25 ° C. for 7 days, the filling liquid is analyzed, and the residual solvent concentration is analyzed. However, it is important to wash thoroughly until it is preferably 0.5 ppm or less, more preferably 0.1 ppm or less.

By insolubilizing the hydrophilic polymer compound,
The properties of the hydrophilic polymer compound are suppressed, and the surface and the intermediate layer of the hollow fiber become hydrophobic close to polysulfone, and endotoxin and its fragments with molecular weights as small as several thousand are trapped and adsorbed, and its permeation is reduced. Restrained,
The object of the present invention is achieved.

The polysulfone hollow fiber artificial kidney of the present invention has an albumin permeability of 0.2% or more and 3.0% or less,
It is preferably 0.6% or more and 2.0% or less, and the endotoxin permeability is 0.02% or less, preferably 0.1% or less.
0.1% or less, and further characterized by being filled with water.

In the present invention, the transmittance of endotoxin is measured by a colorimetric method using an end space method set manufactured by Seikagaku Corporation.

Next, the polysulfone-based hollow fiber artificial kidney of the present invention will be specifically described. The polysulfone-based hollow fiber artificial kidney of the present invention comprises a hollow fiber membrane made of a polysulfone-based resin containing a hydrophilic polymer compound as described above.

Examples of the polysulfone resin used in the present invention include polysulfone resins such as polyether sulfone constituted by repeating units represented by the following formula (I) or (II).

[0017]

Embedded image (In the formula, n represents a positive integer.) Such a polysulfone-based resin is commercially available from Amoco, BASF, ICI, or the like. In particular, the polysulfone-based resin has a structure represented by the above formula (I). Product name P of Amoco
-3500, or an equivalent thereof, is preferred. However, to control the viscosity of the stock solution, the product name of Amoco P-170 was used.
Needless to say, 0 and the like can be mixed and used.

The hydrophilic polymer compound used in the present invention includes polyvinylpyrrolidone, polyethylene glycol, polyglycol monoester, a copolymer of polyethylene glycol and polypropylene glycol,
Examples include water-soluble derivatives of cellulose and polymer compounds having excellent hydrophilicity such as polysorbate, and polyvinylpyrrolidone is particularly preferable. Polyvinylpyrrolidone is produced by polymerization of N-vinyl-2-pyrrolidone, and is, for example, commercially available from BASF, GAF, or the like, and has a weight average molecular weight of 30,000 such as K-30 or K-90. The above are preferably used.

The hollow fiber membrane constituting the hollow fiber type artificial kidney of the present invention discharges a spinning stock solution obtained by dissolving the above-mentioned polysulfone resin and a hydrophilic polymer compound in a solvent, and injects an injection solution into the center. It is discharged from an annular slit die that can be produced by spinning by a so-called dry-wet spinning method.

As the solvent used in this case, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide and the like can be used alone or as a mixture. Among them, dimethylacetamide is a preferable solvent because a hollow fiber membrane having good characteristics for an artificial kidney can be obtained by combining it with water added in a small amount as a molecular weight or pore size regulator of the raw material polymer.

The concentration of the polysulfone resin in the spinning solution of the method for producing a hollow fiber membrane of the present invention is preferably 14 to 2
It is in the range of 5% by weight, more preferably in the range of 17 to 19% by weight. If the concentration is too low, the strength of the hollow fiber decreases, and if the concentration is too high, there remains a problem that the permeability of the hollow fiber membrane decreases.

The concentration of the hydrophilic polymer is preferably in the range of 4 to 15% by weight, more preferably 7 to 10% by weight.
% By weight. If the concentration is too low, there will be a problem of so-called residual blood, in which blood cells tend to adhere after clinical use, leaving blood, and if the concentration is too high, there remains a problem that the strength of the hollow fiber during spinning decreases.

Particularly, in order to obtain a hollow fiber membrane having good characteristics as an artificial kidney by spinning at high speed in consideration of economy, the viscosity of the spinning stock solution is important. If the viscosity is too low, the breakage of the yarn in the dry portion and the variation in the diameter of the hollow fiber increase, and it is difficult to control the albumin transmittance, which is not preferable. Also, when the viscosity is high, the dispersion of the membrane pressure of the hollow fiber becomes large, and the ability to remove uretoxin decreases, which is not preferable.

Therefore, in the spinning dope of the present invention, when dimethylacetamide is used as the solvent,
The viscosity at 0 ° C is in the range of 25 to 130 poise (20 ° C
Is preferably about 35 to 170 poise), and 40 to
A range of 110 poise is more preferred.

The viscosity can be adjusted by adjusting the concentration and molecular weight of the polysulfone resin in the spinning dope and the concentration and molecular weight of the hydrophilic polymer. The most preferable method is to change the molecular weight of the hydrophilic polymer. It is. That is, for example, polyvinylpyrrolidone having a weight average molecular weight of about 40,000 (manufactured by BASF; trade name K-30) and polyvinylpyrrolidone having a molecular weight of about 1,100,000 (manufactured by BASF; trade name K-90) are mixed. In this method, the desired viscosity is obtained by changing the mixing ratio.

A specific preferred example is as follows. When dimethylacetamide is used as a solvent, the concentration of polysulfone (trade name: P-3500) manufactured by Amoco is 18% by weight, and the concentration of polyvinylpyrrolidone is 9% by weight. The mixing ratio of the trade name K-30 and the trade name K-90 is about 9 / 0-5
/ 4, more preferably about 8/1 to 5.5 / 3-5.
Range.

In the spinning dope of the present invention, it is preferable to add a small amount of water as a pore size regulator for the hollow fiber membrane. When dimethylacetamide, which is the most preferred solvent, is used, the preferred amount y (% by weight) of water contained in the stock solution is determined by the viscosity of the stock solution, and is represented by the following formula: -0.01x + 1.45≤y≤-0.01x + 2 .25 is obtained, a hollow fiber membrane having good characteristics can be obtained. Amount of water contained in stock solution y (% by weight)
More preferably satisfies the following expression: -0.01x + 1.65 ≦ y ≦ −0.01x + 2.05. Where x
Is the viscosity (poise) at 30 ° C. of the spinning dope, and x
Is in the range of 25 to 130 poise, preferably 40 to 110
Poise range.

When the amount of water added is small, the formation of white turbidity due to the long-term storage of the spinning solution (polysulfone oligomer is likely to crystallize and become cloudy, and as turbidity progresses, breakage of yarn during spinning is observed. Is suppressed, but the pore size becomes small, and the ability to remove substances having a molecular weight of 10,000 or more, such as β ₂ -microglobulin, is undesirably reduced. Conversely, if the amount of water added is large, the stability of the spinning dope becomes poor, causing cloudiness, and the transmittance of albumin is undesirably too high.

Further, in the method for producing a hollow fiber membrane used in the present invention, the injection liquid is discharged from the center of the mouthpiece, and the inner surface of the hollow fiber is controlled by its coagulability, so that good properties as an artificial kidney can be obtained. To obtain a film having Injection liquids are generally used for the purpose of slowly coagulating a spinning dope from the inner surface of a hollow fiber to form a dense active layer of a separation membrane. Organic solvents alone or mixtures with water can be used.

In the present invention, a mixed solution of the same solvent as the solvent used for the spinning dope and water is preferable, particularly for easy recovery and high performance, and the most preferable solvent is dimethylacetamide and water. Mixed solvents are more preferred. It is also a preferable method to add a small amount of polyvinylpyrrolidone to the injection solution.

When a mixed solvent of dimethylacetamide and water is used, in order to obtain a membrane having good characteristics as the artificial kidney of the present invention, the amount of water contained in the infusate z
(% By weight) is defined by the viscosity of the stock solution, and preferably falls within a range satisfying the following formula: 0.14x + 25.5 ≦ z ≦ 0.14x + 37.5. It is more preferable that the amount z (% by weight) of water contained in the infusion be in the range satisfying the following expression: 0.14x + 28.5 ≦ z ≦ 0.14x + 34.5. Where x
Is the viscosity (poise) at 30 ° C. of the spinning dope, and x
Is in the range of 25 to 130 poise, preferably 40 to 110
Poise range.

Further, as a hollow fiber membrane for an artificial kidney, a membrane having better properties can be obtained by using both the amount y (% by weight) of water in a stock solution and the amount z (% by weight) of water in an infusion solution. Is obtained by satisfying each of the above expressions.

When the amount of water is small, the solidification of the spinning solution is slow and the solidification from the inner surface is slow, so that thread breakage easily occurs in the dry portion and the permeability of proteins such as albumin becomes too high. There is a tendency. Conversely, when the amount of water is large, the performance of removing substances having a high molecular weight such as β ₂ -microglobulin decreases, and when the amount of water further increases, the performance of removing low-molecular substances also deteriorates.

The hollow fiber membrane of the present invention is prepared by a wet spinning method using an undiluted spinning solution and an injection solution set as described above and directly leading a coagulation bath from an annular slit-type die, or a method in which a hollow fiber from a die is once in a gas phase. And then spun by a dry-wet spinning method that leads into a coagulation bath. At this time, in order to obtain good performance, a dry-wet method in which the yarn is run in the gas phase (dry section) for preferably 0.1 to 1.0 second, more preferably 0.2 to 0.8 second. Spinning is preferred.

As the condition of the dry section, a relative humidity of 40% or more is required, and the dry section is preferably brought into contact with a humidified humid air having a relative humidity of 70% or more, more preferably 8% or more.
Good performance can be obtained by contact in a humid air stream of 0% or more.

Next, the hollow fiber stock solution spun from the die in this manner is led to a coagulation bath. In the coagulation bath, it is miscible with the solvent, but the polysulfone resin comes into contact with the coagulation liquid, which is a non-solvent having coagulation ability, and forms a membrane with a large pore sponge-like structure as a support layer from the outer surface side. .
As the coagulating liquid, a non-solvent alone or a mixture of two or more kinds can be used, but from the viewpoint of recovery of the solvent, a mixed solution of the same solvent as the spinning dope and water is preferable.

The hollow fiber that has exited the coagulation bath is washed with water to remove most of the solvent components, then immersed in a moisturizing material solution, cut into a predetermined length, and bundled into a predetermined number of yarns. Then, the wet retaining material solution in which the injection liquid inside the hollow fiber is replaced at the time of the immersion is drained to form a hollow fiber bundle.

One of the features of the production of the hollow fiber artificial kidney of the present invention is that the hydrophilic polymer compound is localized on the inner surface of the hollow fiber membrane and in the vicinity thereof. For this reason, it is important to remove the hydrophilic polymer compound from the outer surface side by water washing in the coagulation bath and the washing step immediately after the coagulation bath, and further in the final washing step after module assembly. As a guide for washing, the ratio of the hydrophilic polymer compound in the material polymer (polysulfone + hydrophilic polymer compound) in the stock solution is defined as C ₁ (% by weight), and the hydrophilic polymer compound in the hollow fiber of the product module is used. Is sufficiently washed so that the value of C ₂ / C ₁ is 0.1 to 0.5, preferably 0.15 to 0.35 when the ratio of C _{2 is} (weight%). In the present invention, the value of C ₂ is
It is 2 to 10% by weight, preferably 3 to 7% by weight. When the remaining amount of the hydrophilic polymer compound is large, there is a problem such as a decrease in the strength of the hollow fiber, and when too small, the effect of hydrophilizing the inner surface of the hollow fiber is reduced. For this reason, the water washing immediately after the coagulation bath can be carried out with water at about room temperature, but preferably with 50 ° C. or higher, more preferably 75 ° C. or higher, and the outer layer of the hollow fiber together with most of the solvent components. And the hydrophilic polymer compound in the intermediate layer.

Although it is difficult to accurately quantify the distribution state of the hydrophilic polymer compound remaining in the hollow fiber membrane of the product module, in the case of polyvinylpyrrolidone, which is the most preferred hydrophilic polymer compound, the following method is used. An approximate value can be determined.

Osminium staining (OsO ₄ staining), which can well stain polyvinylpyrrolidone, is performed, and the cross section of the hollow fiber membrane is observed with a transmission electron microscope. The distribution of black spots indicates that the hollow fiber membrane of the present invention has Is that at least half of the polyvinylpyrrolidone is distributed in a 1 / 10th film thickness portion from the inner surface side.

As a method of indirectly but easily confirming whether or not these washings have been sufficiently performed, there is a method of measuring the concentration of the solvent remaining in the hollow fiber membrane of the product module. Specifically, the sterilized product is allowed to stand at 25 ° C. for 7 days, and the filling liquid is measured by gas chromatography-mass spectrometry.
m is essential, and preferably, the washing is performed so as to be 0.1 ppm or less.

The wetting agent used in the present invention includes alcohols and inorganic salts which can prevent drying even when a bundle of hollow fibers such as glycerin, ethylene glycol, polypropylene glycol and polyethylene glycol is left in the air. Can be used, but glycerin is particularly preferred.

The hollow fiber bundle thus obtained is assembled (modulated) into an artificial kidney by a usual method.

That is, a yarn bundle is inserted into a case made of a polystyrene resin or the like, and tube sheets are formed on both ends of the case using a potting material such as polyurethane and centrifugal force is applied. Shape.

Next, a trace amount of the solvent or the moisturizing agent remaining inside the hollow fiber membrane is removed by washing with water, and sterilized while being filled with water to obtain a product artificial kidney. This water washing can be performed with water near room temperature, but it requires about 2 hours at 55 ° C. and about 15 minutes at 80 ° C. Therefore, washing with heated water at 55 ° C. or more is preferable. Further, it is also possible to carry out repeated washing such as performing a short-time washing, keeping the temperature at 50 ° C. or higher, and then performing a short-time washing. In this final washing, in addition to washing from the outer surface side, it is also a preferable embodiment to wash the surface with a part of water or to wash while filtering through a membrane.

In the present invention, it is important that the washing is sufficiently performed to reduce the residual amount of the solvent or the wet holding material which has the effect of suppressing the insolubilization of the hydrophilic polymer compound due to the crosslinking reaction in the next step. . As a standard for washing, as described above, the concentration of the solvent in the filling liquid after leaving the sterilized product at 25 ° C. for 7 days was measured by gas chromatography-mass spectrometry to be 0.5 ppm. Below, preferably 0.
Wash thoroughly until 1 ppm or more.

Sterilization is preferably performed in a state filled with water using gamma rays (γ rays) or electron beams.

In the present invention, when polyvinylpyrrolidone, which is the most preferred hydrophilic polymer compound, is used, irradiation with γ-rays at a dose in the range of about 20 KGy to 35 kGy will result in insolubilization by crosslinking of polyvinylpyrrolidone and medical equipment. Can be performed at the same time, which is the most practical sterilization method.

Simultaneous insolubilization by cross-linking of polyvinylpyrrolidone by this sterilization has the effect of suppressing elution and improving the safety of the product. Also,
Compared with the case of not insolubilizing by this method, the effect of polyvinylpyrrolidone as a hydrophilizing agent for the hollow fiber, particularly the intermediate layer, is suppressed, the efficiency of capturing endoxins and fragments thereof is increased, and the object of the present invention is achieved. You.

In order to insolubilize polyvinylpyrrolidone by crosslinking, it is needless to say that irradiation may be performed separately prior to sterilization. However, it is better to simultaneously perform crosslinking and sterilization by one irradiation. It is also preferable to obtain a high-performance film.

[0051]

The present invention will be specifically described below with reference to examples.
The present invention is not limited by this. Also,
The characteristics of the present invention were evaluated by the following methods.

[Water permeability] A length of about 15 c obtained by cutting the case of a product artificial kidney completed by performing γ-ray sterilization
A small glass tube module was prepared using 30 hollow fibers having a length of m, and the pressure difference between the outside and inside of the membrane, that is, the membrane pressure difference was about 1
Measure the amount of water permeation at 00 mmHg and calculate m1 / hr · mm
It was expressed in Hg · m ² .

[0053] the urea and vitamin B ₁₂ dialysance of] urea 60g and vitamin B ₁₂ 1.2 g was dissolved in water 60 liters, blood side flow rate 200m1 / min, the dialysate side flow rate 500 ml / min, the filtration rate 10M1 / min
The dialysance of the blood-side reference and the dialysate-side reference was calculated by measuring the concentrations at the blood-side inlet and outlet of the dialyzer and the dialysate-side inlet and outlet, respectively, and the average value was used to calculate m1
/ Min.

[Albumin Permeability] Hematocrit 3
Bovine blood 21 at 0%, protein concentration 6 g / d1, and 37 ° C.
Is placed in a beaker, the blood side flow rate is 200 ml / min, and the transmembrane pressure difference is circulated at about 100 mmHg for 1 hour, and the filtrate obtained during that time is returned to the beaker. Thereafter, three filtrates are collected at intervals of 15 minutes with a transmembrane pressure difference of about 60 mmHg. The albumin concentration in the plasma obtained by centrifuging bovine blood was measured by the BCG method (Wako Pure Chemical Industries, Ltd.), and the albumin concentration in the filtrate was measured by the CBB method (Tokyo Kasei). From the average value of the three filtrates, albumin was determined. Calculate the transmittance.

[Spinning stock solution viscosity] Using a B-type viscosity solution (DV-BII type digital viscometer, Tokimec Co., Ltd.), a spinning stock solution of 300 ml or more is collected and measured without being affected by the inner diameter of the container.

[Permeability of endotoxin] Tap water having an endotoxin concentration of 2500 pg-ml or more from a river as a water source was completely filtered from the dialysate side to the blood side of the module having a membrane area of 1.3 m ² at 500 ml / min for 10 minutes. About 200 ml is collected at the blood side outlet, and the endotoxin concentration is measured.

For the measurement of the endotoxin concentration, an Endosciece ES-6 set of Seikagaku Corporation was used.
A Toxicolor System DIA set is also used to increase measurement sensitivity. Toxicolor system Et for calibration curve
-1 set of E. coliOIII: B4 (1 pg =
0.0029 EU).

(Example 1) 18 parts of polysulfone (“P-3500” manufactured by Amoco) (hereinafter, “parts” means “parts by weight”) and polyvinylpyrrolidone (B
6 parts of ASF “K-30”; molecular weight of about 40,000) and polyvinylpyrrolidone (BASF “K-90”);
(Molecular weight: about 1,100,000) was added to a mixed solution of 71.95 parts of dimethylacetamide and 1.05 parts of water, and dissolved by stirring at 80 ° C. for 12 hours.
A spinning dope was prepared.

The undiluted spinning solution was discharged from the annular slit die at 30 ° C., and dimethylacetamide 6 was discharged from the center of the die.
An injection solution prepared by mixing 1 part with 39 parts of water was injected. The length of the dry portion is 250 mm, and the spinning speed is 40 m / m while flowing humid air having a relative humidity of 88% through the portion.
The fiber was guided to a coagulation valley at 40 ° C. (dimethylacetamide / water (weight ratio) = 20/80), and the hollow fiber discharged from the coagulation bath was washed from outside with hot water at 80 ° C. It was immersed in an aqueous solution containing glycerin by weight. The hollow fiber had an inner diameter of 200 microns and an outer diameter of 280 microns, and the hollow fiber bundle was a collection of 10,608 hollow fibers.

This hollow fiber bundle is inserted into a case for an artificial kidney having an inner diameter of 40 mm, temporary caps are attached to both ends, and polyurethane is poured from the dialysate-side inlet at the place of rotational centrifugal force. Allowed to solidify. Next, the temporary cap was removed, the vicinity of the ends of the polyurethane and the hollow fiber bundle protruding from both ends of the case was cut, a header cap was attached, and a leak test was performed using 0.8 kg / cm ² of pressurized air. Was.

Next, 85 modules that passed the leak test
After washing with pure water passing through a reverse osmosis membrane at 30 ° C. for 30 minutes and packaging, it is irradiated with 32 KGy of γ-ray and sterilized to insolubilize polyvinylpyrrolidone at the same time, and filled with water having an effective length of 195 mm and an effective area of 1.3 m ^2. An artificial kidney dialyzer has been created. This dialyzer passed all the criteria for the dialysis-type artificial kidney device approval standard. The water permeability of the hollow fiber cut out from this module is 840 m1 / hr · mmH
g · m ² , and the albumin transmittance of the module is 1.3.
%, Dialysance of urea 194m1 / min, the dialysance of vitamin B ₁₂ was 142m1 / min. Further, the content of the polyvinylpyrrolidone component in the hollow fiber polymer of this module was 4.8%, and the residual amount of dimethylacetamide in the filling liquid was 0.04 ppm.

Further, the endotoxin permeability was measured using the obtained hollow fiber artificial kidney dialyzer. Although the endotoxin concentration at the dialysate-side inlet was 2840 pg / ml, the endotoxin concentration at the blood-side outlet was less than the detection limit of 0.1.
It was 2 pg / ml or less, and the endotoxin permeability was 0.01% or less. Further, when a hollow fiber having a length of 3 cm obtained by cutting out from the dialyzer was impregnated with dimethylacetamide as a solvent, a transparent gel-like material containing polyvinylpyrrolidone as a main component in a hollow fiber form was obtained. In addition, insolubilization due to a crosslinking reaction was observed.

Example 2 18 parts of polysulfone (“P-3500” manufactured by Amoco) and polyvinylpyrrolidone (B
6 parts of "K-30" manufactured by ASF and 3 parts of polyvinylpyrrolidone ("K-90" manufactured by BASF) are added to a mixed solution of 71.85 parts of dimethylacetamide and 1.15 parts of water, and 90 The solution was dissolved for 12 hours while keeping the temperature at ° C to prepare a spinning stock solution. This spinning stock solution was discharged from the annular slit die at 40 ° C., and an injection solution prepared by mixing 59 parts of dimethylacetamide and 41 parts of water was injected from the center of the die. The length of the dry portion was 350 mm, and the spinning speed was 42 m /
The mixture was then introduced into a coagulation bath at 45 ° C. for min, and an artificial kidney dialyzer was prepared in the same manner as in Example 1 below.

The thus obtained effective area 1.3 m
The water permeability of the hollow fiber cut from the dialyzer of No. ² is 820m
1 / hr · mmHg · m ² , the transmittance of albumin is 0.7%, and the dialysance of urea and vitamin B12 is 193 ml / min and 142 ml / min, respectively.
Met. The content of the polyvinylpyrrolidone component in the hollow fiber polymer of this module was 5.3%, and the concentration of dimethylacetamide in the filling solution was 0.05 ppm.
Met.

Further, the transmittance of endotoxin was measured using the obtained hollow fiber type artificial kidney dialyzer. Although the endotoxin concentration at the dialysate-side inlet was 2840 pg / ml, the endotoxin concentration at the blood-side outlet was less than the detection limit of 0.1.
It was 2 pg / ml or less, and the endotoxin permeability was 0.01% or less. Further, when a hollow fiber having a length of 3 cm obtained by cutting out from the dialyzer was impregnated with dimethylacetamide as a solvent, a transparent gel-like material containing polyvinylpyrrolidone as a main component in a hollow fiber form was obtained. In addition, insolubilization due to a crosslinking reaction was observed.

Example 3 An artificial kidney dialysis was performed in the same manner as in Example 2 except that the stock solution prepared in Example 2 was used and an injection solution prepared by mixing 56 parts of dimethylacetamide and 44 parts of water was used. A vessel was made.

The thus obtained effective area of 1.3 m
The water permeability of the hollow fiber cut from the dialyzer of No. ² is 760m
1 / hr · mmHg · m ² , the albumin transmittance was 0.2%, and the dialysance of urea and vitamin B ₁₂ was 192 ml / min and 140 ml / min, respectively. Further, the content of the polyvinylpyrrolidone component in the hollow fiber polymer of this module was 5.4%, and the concentration of dimethylacetamide in the filling solution was 0.07 ppm.

Further, the transmittance of endotoxin was measured using the obtained hollow fiber artificial kidney dialyzer. Although the endotoxin concentration at the dialysate-side inlet was 2840 pg / ml, the endotoxin concentration at the blood-side outlet was less than the detection limit of 0.1.
It was 2 pg / ml or less, and the endotoxin permeability was 0.01% or less. Further, when a hollow fiber having a length of 3 cm obtained by cutting out from the dialyzer was impregnated with dimethylacetamide as a solvent, a transparent gel-like material containing polyvinylpyrrolidone as a main component in a hollow fiber form was obtained. In addition, insolubilization due to a crosslinking reaction was observed.

(Comparative Example 1) A commercially available polysulfone artificial kidney dialyzer [U] (albumin permeability: 0) which is a steam-sterilized product using polyvinylpyrrolidone as a hydrophilic polymer and which is not insolubilized by crosslinking of polyvinylpyrrolidone. .2%) and [N] (0.8% albumin transmittance), the endotoxin transmittance was measured in the same manner as in Example 1 above. As a result, the endotoxin concentration at the dialysate-side inlet was 2,830 pg / ml, the blood-side outlet concentrations were 0.8 pg / ml and 11.9 pg / ml, respectively, and the endotoxin permeability was 0.03% and 0.1, respectively.
42%, and permeation of endotoxin was observed. The effective membrane area of each of these dialyzers was 1.3 m ² .

When hollow fibers cut from these two commercial products were impregnated with dimethylacetamide in the same manner as in Example 1, both were dissolved, and a gel-like material having a shape was observed. Did not.

[0071]

According to the present invention, the permeation of endotoxin by back filtration or back diffusion is observed despite high water permeability, high uremic substance removal performance, and moderate albumin permeability. An artificial kidney with excellent safety is obtained.

Claims (6)

[Claims] 1. An albumin transmittance of 0.2% or more.
0% or less and the endotoxin permeability is 0.0
A polysulfone-based hollow fiber-type artificial kidney characterized by being 2% or less. 2. The polysulfone hollow fiber artificial kidney according to claim 1, wherein the albumin transmittance is 0.6% or more and 2.0% or less. 3. The endotoxin has a permeability of 0.01.
% Or less, the polysulfone hollow fiber artificial kidney according to claim 1 or 2. 4. A hollow fiber obtained by spinning a spinning dope comprising a polysulfone-based resin, a water-soluble hydrophilic polymer compound and a solvent, washing the outer surface of the hollow fiber to wash the hollow fiber. While removing the compound and the solvent, the hydrophilic polymer compound is localized on the inner surface of the hollow fiber membrane and in the vicinity thereof, and a gamma ray or an electron beam is charged in a state where the module containing the hollow fiber is filled with water. And producing a polysulfone-based hollow fiber artificial kidney, wherein the remaining hydrophilic polymer compound is crosslinked and insolubilized simultaneously with sterilization. 5. The washing of the hollow fiber from the outer surface, wherein the ratio of the hydrophilic polymer compound to the total of the polysulfone resin and the hydrophilic polymer compound in the spinning solution is C ₁ (% by weight). When the ratio of the hydrophilic polymer compound to the total of the polysulfone-based resin and the hydrophilic polymer compound in the hollow fiber in the module containing the hollow fiber is C ₂ (% by weight), C ₂ / C ₁ value is 0.1
5. The method according to claim 4, wherein the cleaning is performed until the value becomes 0.5.
A method for producing the polysulfone-based hollow fiber artificial kidney according to the above. 6. The washing of the outer surface of the hollow fiber until the solvent component in the filling water in the module storing the hollow fiber becomes 0.5 ppm or less. 5. The method for producing a polysulfone hollow fiber artificial kidney according to 5.